A synthetic resveratrol analog termed Q205 reactivates latent HIV-1 through activation of P-TEFb

Liang, Taizhen; Wu, Ziyao; Li, Yibin; Li, Chao; Zhao, Kangni; Qiao, Xinman; Duan, Hong‐Quan; Zhang, Xuanxuan; Liu, Shuwen; Xi, Baomin; Li, Lin

doi:10.1016/j.bcp.2021.114901

Cited by 3 publications

(4 citation statements)

References 72 publications

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“…These previous results, combined with those described here, support the hypothesis that hopeaphenol is likely a broad-spectrum natural antiviral compound. Structurally, hopeaphenol is a tetramer of resveratrol molecules, and interestingly both resveratrol and resveratrol analogs are reported to promote HIV latency reversal and viral expression through a variety of mechanisms, including stimulating histone acetylation, heat shock factor 1 expression, CDK9 phosphorylation, p-TEFb activation, and EGR1 expression ( 36 – 38 ). Thus, further structure-activity relation studies with both stilbenoid and resveratrol analogues may identify chemical moieties that underlie both HIV latency reversal and HIV silencing in T cells.…”

Section: Discussionmentioning

confidence: 99%

The Natural Stilbenoid (–)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9

Tietjen

Schonhofer

Sciorillo

et al. 2023

Antimicrob Agents Chemother

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Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to harbor replication-competent and transcriptionally active virus in infected cells, which in turn can lead to ongoing viral antigen production, chronic inflammation, and increased risk of age-related comorbidities. To identify new agents that may inhibit postintegration HIV beyond cART, we screened a library of 512 pure compounds derived from natural products and identified (–)-hopeaphenol as an inhibitor of HIV postintegration transcription at low to submicromolar concentrations without cytotoxicity. Using a combination of global RNA sequencing, plasmid-based reporter assays, and enzyme activity studies, we document that hopeaphenol inhibits protein kinase C (PKC)- and downstream NF-κB-dependent HIV transcription as well as a subset of PKC-dependent T-cell activation markers, including interleukin-2 (IL-2) cytokine and CD25 and HLA-DRB1 RNA production.

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Section: Discussionmentioning

confidence: 99%

The Natural Stilbenoid (–)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9

Tietjen

Schonhofer

Sciorillo

et al. 2023

Antimicrob Agents Chemother

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“…The synergistic effects of multiple drug applications were examined using the Bliss independence model, as previously described. 59 Cell Transfection and Luciferase Assays. 293T cells at 2 × 10 5 cells/well were seeded into a 6-well plate at 37 °C for 24 h, followed by cotransducing with 500 ng of VSV-G glycoprotein expression vector and 500 ng of lentiviral packaging construct psPAX2 with pEZ-Lv242-Tat or empty vector plasmids using polyject (Invitrogen) according to the manufacturer's instructions.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The reactivation of latent HIV-1 expression by indicated drug alone and the combination of obatoclax with other LRAs in latently HIV-1 infected cell lines was evaluated by ELISA. The synergistic effects of multiple drug applications were examined using the Bliss independence model, as previously described …”

Section: Methodsmentioning

confidence: 99%

Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells

Zhou,

Li,

Xia

et al. 2023

ACS Infect. Dis.

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The implementation of combined antiretroviral therapy (cART) has rendered HIV-1 infection clinically manageable and efficiently improves the quality of life for patients with AIDS. However, the persistence of a latent HIV-1 reservoir is a major obstacle to achieving a cure for AIDS. A “shock and kill” strategy aims to reactivate latent HIV and then kill it by the immune system or cART drugs. To date, none of the LRA candidates has yet demonstrated effectiveness in achieving a promising functional cure. Interestingly, the phosphorylation and activation of antiapoptotic Bcl-2 protein induce resistance to apoptosis during HIV-1 infection and the reactivation of HIV-1 latency in central memory CD4+ T cells from HIV-1-positive patients. Therefore, a Bcl-2 antagonist might be an effective LRA candidate for HIV-1 cure. In this study, we reported that a pan-Bcl-2 antagonist obatoclax induces HIV-1 reactivation in latently infected cell lines in vitro and in PBMCs/CD4+ T cells of HIV-infected individuals ex vivo. Obatoclax promotes HIV-1 transcriptional initiation and elongation by regulating the NF-κB pathway. Obatoclax activates caspase 8 and does not induce the phosphorylation of the antiapoptotic protein Bcl-2 in latent HIV-1 infected cell lines. More importantly, it preferentially induces apoptosis in latently infected cells. In addition, obatoclax exhibited potent anti-HIV-1 activity on target cells. The abilities to reactivate latent HIV-1 reservoirs, inhibit HIV-1 infection, and induce HIV-1 latent cell apoptosis make obatoclax worth investigating for development as an ideal LRA for use in the “shock and kill” approach.

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“…A preliminary mechanistic study revealed that the latency-reversal potency of Q205 was attributable to the activation of P-TEFb and promotion of Tat-mediated HIB-1 transcription and binding of RNAPII to the HIV-1 5 -LTR promoter. The results evinced that identification of promising LRAs from naturally available polyphenols and/or chemically optimized resveratrol derivatives might be a feasible and practicable alternative [131].…”

Section: Polyphenolsmentioning

confidence: 97%

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

Wang

Wei

et al. 2022

Molecules

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The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called ‘shock-and-kill’ regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection.

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A synthetic resveratrol analog termed Q205 reactivates latent HIV-1 through activation of P-TEFb

Cited by 3 publications

References 72 publications

The Natural Stilbenoid (–)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9

The Natural Stilbenoid (–)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9

Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

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